Graphical Abstract:

Abstract:

Background and Objective: Sphingolipid metabolites, including ceramide, sphingosine,
and their phosphorylates (ceramide-1-phosphonate [C1P] and sphingosine-1-phosphate [S1P]), regulate
diverse cellular processes including apoptosis, the cell cycle, and cellular differentiation. Recent
studies have shown that these sphingolipid metabolites are generated in response to ototoxic agents
and play important roles in determining the fate of cochlear hair cells in ototoxic injury.

Methods: This review summarizes the current knowledge on the roles of sphingolipid mediators in
cochlear ototoxicity.

Results: During ototoxicity, ceramide is mainly generated via sphingomyelinase in the cochlea
through a ceramide/sphingomyelin cycle from sphingomyelin. The generated ceramide is converted to
other sphingolipid mediators. Ceramide and sphingosine accelerate cochlear hair cell death induced
by ototoxic agents, while, C1P and S1P, on the other hand, protect cochlear hair cells. Hair cell protection
of S1P is mediated by S1P receptor subtype 2 (S1PR2).

Conclusion: Sphingolipid mediators play important roles in cochlear hair cell survival or death in ototoxic
injury.

Abstract:Background and Objective: Sphingolipid metabolites, including ceramide, sphingosine,
and their phosphorylates (ceramide-1-phosphonate [C1P] and sphingosine-1-phosphate [S1P]), regulate
diverse cellular processes including apoptosis, the cell cycle, and cellular differentiation. Recent
studies have shown that these sphingolipid metabolites are generated in response to ototoxic agents
and play important roles in determining the fate of cochlear hair cells in ototoxic injury.

Methods: This review summarizes the current knowledge on the roles of sphingolipid mediators in
cochlear ototoxicity.

Results: During ototoxicity, ceramide is mainly generated via sphingomyelinase in the cochlea
through a ceramide/sphingomyelin cycle from sphingomyelin. The generated ceramide is converted to
other sphingolipid mediators. Ceramide and sphingosine accelerate cochlear hair cell death induced
by ototoxic agents, while, C1P and S1P, on the other hand, protect cochlear hair cells. Hair cell protection
of S1P is mediated by S1P receptor subtype 2 (S1PR2).

Conclusion: Sphingolipid mediators play important roles in cochlear hair cell survival or death in ototoxic
injury.